The type I receptor tyrosine kinase family is comprised of four closely related receptors: ErbB1 (EFGR or HER1), ErbB2 (HER2), ErbB3 (HER) and ErbB4 (HER4). These receptors are transmembrane glycoproteins which contain an extracellular domain for ligand binding and, with the exception of HER3, an intracellular catalytically active tyrosine kinase domain. These receptors transmit extracellular signals through the cytosol via a signal transduction cascade to the nucleus. The extracellular signal is transmitted by ligand binding to the dimeric receptor, with the exception of erbB2, of which a high affinity soluble ligand has yet to be identified. After ligand binding, the type I receptor tyrosine kinases either homodimerize or heterodimerize with another member of the subfamily of receptors (Lemmon M A, Experimental Cell Research (2009), 315, 638-648). ErbB2 participates in this process by heterodimerization. In fact, it has been shown that ErbB2 is the preferred heterodimerization partner (Mehelsohn Oncogene 2000). Dimerization leads to activation of the ErbB receptors by autophosphorylation of the intracellular domain. This autophosphorylation recruits adaptor proteins and leads to a phosphorylation cascade that transmits the signal throughout the cell. The type I receptor tyrosine kinase family (ErbB family) signals through the ras/raf/MEK/MAPK pathway as well as the PI3K/Akt pathway. These signaling pathways lead to both cell proliferation and cell survival through inhibition of apoptosis.
It has been demonstrated that ErbB family receptors play important roles in cancer (Burgess A W, Growth Factors (2008), 26(5), 263-74). Squamous carcinomas of the head and neck, and lung express high levels of EGFR. Also, constitutively active EGFR has been found in gliomas, breast cancer and lung cancer (Salomon, et al., Critical Review Oncology/Hematology (1995), 19, 183-232; Klapper, et al., Advanced Cancer Research (2000), 77, 25-79, and Hynes and Stem, Biochimica et Biophysica Acta (1994), 1198, 165-184). ErbB2 overexpression occurs in approximately 30% of all breast cancer (Milanezi, et al., Expert Review Molecule Diagnosis. (2008), 8(4), 417-34). It has been also implicated in other human cancers including colon, ovary, bladder, stomach, esophagus, lung, uterus and prostate. ErbB2 overexpression has also been correlated with poor prognosis in human cancer, including metastasis, and early relapses (Baselga J and Swain S M, Nature Review of Cancer (2009), 9(7), 463-75)
The type I tyrosine kinase receptor family has been an active area of anti-cancer research (O'Donovan and Crown Anticancer Res. (2007) 27(3A), 1285-94). Although several inhibitors of the EGFR and the ErbB2 signaling pathway have demonstrated clinical efficacy in cancer treatment and a few molecules have been approved by the FDA, due to the prevalence and complexity of cancers, there remains a need for better treatment for cancers such as small molecule pharmaceuticals with better pharmacological properties and/or lower toxcitiy.